Grants Support Study of New Genes, New Drug Discovery Strategies for ALS

MDA’s winter 2013 round of grants includes $3.6 million in funds for research into the causes of, and treatments for, amyotrophic lateral sclerosis.

Some of the grants seek a better understanding of mutated genes such as C9ORF72, TDP43 and FUS, which have been implicated in ALS. The role played by TDP43 protein in neuron degeneration — even in people with ALS who do not have a mutation in this gene — also is being studied.

Several grants are aimed at advancing the development of drugs for ALS, including identifying new drug targets, and testing existing drugs used in Alzheimer’s disease and diabetes.

ALS and another neuromuscular disease, inclusion-body myositis, each can be caused by mutations in the VCP gene. Three groups of researchers are exploring the overlap of these two diseases.

Twelve new grants totaling $3.6 million have been awarded in support of research studies that will explore the causes of, and potential treatments for, amyotrophic lateral sclerosis (ALS).

“This is truly an exciting time in ALS research,” Jane Larkindale, MDA vice president of research, said about the new grants, which took effect Feb. 1. She noted that recent discoveries of new disease-causing genes for ALS have opened new avenues for research into the causes of the disease and potential treatments. "We cannot cure a disease when we don’t know the cause, but we now have so many more pieces of the puzzle on the table that a treatment is looking possible. Projects like these will bring us closer," she said.

Understanding new genes

Perhaps the most significant discoveries about ALS in recent years have involved the identification of genes that cause the disease. The single most common genetic cause is a mutation in a gene called C9ORF72. Jeffrey Rothstein, professor of neurology and neuroscience at Johns Hopkins University in Baltimore, has received MDA funding to develop new cellular models to study the effects of this gene mutation. He will use patient skin cells to create induced pluripotent stem cells, or iPS cells, which can be transformed into motor neurons (the muscle-controlling nerve cells that are lost in ALS) for study in the lab.

Rothstein hopes to find a molecular signature for the disease-causing effects of the mutant C9ORF72 gene. That signature, or biomarker, can then be used to quickly assess the effects of potential therapies on the same cells. “The use of these human cells may allow us to efficiently and quickly develop a drug therapy for the C9ORF72 form of ALS,” he says.

Two other ALS-associated genes, TDP43 and FUS, are also being studied intensively for the clues they may provide. Both genes encode proteins that handle an information molecule in the cell called RNA. Increasing evidence points to defects in RNA handling as a central part of the ALS disease process.

Heather Durham, professor at the Montreal Neurological Institute of McGill University in Quebec, Canada, will study the consequences for motor neurons of mutations in the FUS gene, which she thinks include problems in responding to the level of neuronal activity and stress.

Fenghua Hu, research scientist at Cornell University in Ithaca, N.Y., will study the effects of TDP43 mutation. While the gene mutation is a rare cause of ALS, Hu notes that even in people with ALS who do not have TDP43 mutations, the TDP43 protein often clumps together abnormally, forming aggregates within motor neurons. This phenomenon, Hu notes, “suggests that the misbehavior of TDP43 protein could cause neurodegeneration.” Hu's study of a potential relationship between the protein and neurodegeneration should help researchers develop better targets for therapy in ALS.

New strategies for drug development

Several new projects will explore treatment strategies:

Martha Bhattacharya, a postdoctoral research scholar in developmental biology at Washington University School of Medicine in St. Louis, will study the role of a protein called a G-protein coupled receptor, and another called a protein kinase, in degeneration of axons, the long extensions of neurons. “These receptors are highly desirable drug targets,” Bhattacharya says.

Mohamed Farah, assistant professor of neurology at Johns Hopkins University School of Medicine in Baltimore, will test whether drugs originally designed for Alzheimer’s disease can offer benefit in animal models of ALS by increasing neuronal regeneration and restoring neuromuscular function when given in the early stages of disease.

Giovanni Manfredi, professor of neurology and neuroscience at Weill Medical College of Cornell University in New York, will study whether calcium imbalance in support cells called astrocytes contributes to ALS. His preliminary work has suggested that changes within the astrocyte lead to impaired calcium regulation and secretion of toxic molecules, which in turn cause motor neuron death.

Li Niu, professor and chair of chemistry at the State University of New York at Albany, will study the potential of drugs that reduce the overactivity of a protein called the AMPA receptor on the surface of motor neurons. Too much receptor activity leads to too much excitation of the neuron, and eventually the neuron dies. “Finding inhibitors to control the excessive receptor activity has been a long-pursued strategy for developing ALS drugs,” says Niu.

Sunitha Rangaraju, a postdoctoral research scientist at the Scripps Research Institute in La Jolla, Calif., will test whether compounds that extend the life span of healthy roundworms also can extend life in a worm model of ALS. Studies in roundworms offer scientists the ability to screen many thousands of compounds quickly and to rapidly test the effects of the most promising drug candidates.

Xin Wang, assistant professor of neurosurgery at Harvard Medical School in Boston, will study whether increased cellular signaling of the melatonin system may be neuroprotective, in both cell culture and in a mouse model of ALS.

Daniela Zarnescu, associate professor of molecular and cellular biology at the University of Arizona in Tucson, will investigate whether anti-diabetic drugs may reduce neuron death in ALS. The insulin signaling pathway is believed to be important in neuronal survival, and Zarnescu’s work has led to the identification of several types of drugs currently used to treat diabetes that also reduced death among flies carrying an ALS mutation. “Given that our candidate drugs are already approved for use in humans, our work in the fly model will provide a rapid and cost-effective strategy to help determine whether these drugs could be adapted for the treatment of ALS,” Zarnescu says.

ALS and IBM

A gene that, when mutated, can cause some instances of ALS also is responsible for some instances of another neuromuscular disease, inclusion-body myositis (IBM). The gene, called valosin-containing protein (VCP), helps clear misfolded proteins so that they don’t cause damage within cells. Mutations in VCP lead to protein aggregates within neurons (in ALS) and muscle (in IBM). Three groups of researchers are exploring the overlap of these two diseases and the role of protein aggregation in them:

Benoit Coulombe, director of the Proteomics and Gene Transcription Laboratory at the University of Montréal in Quebec, Canada, will study regulation of VCP, which may go awry when VCP is mutated. Coulombe also will explore whether changes in VCP and the proteins with which it interacts can serve as a biomarker (biological indicator), helping to identify diseased cells and following their response to treatment.

Eric Ross, associate professor of biochemistry and molecular biology at Colorado State University in Fort Collins, will study protein aggregation in a yeast model of ALS/IBM. These aggregates are believed to indicate an ongoing toxic process within the cell, and may be toxic themselves. Ross will be paying particular attention to the spread of misfolding from one cell to the next, which is believed to be an important disease mechanism in protein-misfolding diseases.

Hong Joo Kim, a postdoctoral fellow at St. Jude Children’s Research Hospital in Memphis, Tenn., will be using modern gene-hunting techniques to discover other genes that can cause the same disorder. He will be following up initial discoveries indicating that mutations in certain genes that bind to RNA (related to DNA) may be responsible in some cases where the VCP gene is not involved.